CFH and ARMS2 genetic risk determines progression to neovascular age-related macular degeneration after antioxidant and zinc supplementation

Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E696-E704. doi: 10.1073/pnas.1718059115. Epub 2018 Jan 8.

Abstract

We evaluated the influence of an antioxidant and zinc nutritional supplement [the Age-Related Eye Disease Study (AREDS) formulation] on delaying or preventing progression to neovascular AMD (NV) in persons with age-related macular degeneration (AMD). AREDS subjects (n = 802) with category 3 or 4 AMD at baseline who had been treated with placebo or the AREDS formulation were evaluated for differences in the risk of progression to NV as a function of complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genotype groups. We used published genetic grouping: a two-SNP haplotype risk-calling algorithm to assess CFH, and either the single SNP rs10490924 or 372_815del443ins54 to mark ARMS2 risk. Progression risk was determined using the Cox proportional hazard model. Genetics-treatment interaction on NV risk was assessed using a multiiterative bootstrap validation analysis. We identified strong interaction of genetics with AREDS formulation treatment on the development of NV. Individuals with high CFH and no ARMS2 risk alleles and taking the AREDS formulation had increased progression to NV compared with placebo. Those with low CFH risk and high ARMS2 risk had decreased progression risk. Analysis of CFH and ARMS2 genotype groups from a validation dataset reinforces this conclusion. Bootstrapping analysis confirms the presence of a genetics-treatment interaction and suggests that individual treatment response to the AREDS formulation is largely determined by genetics. The AREDS formulation modifies the risk of progression to NV based on individual genetics. Its use should be based on patient-specific genotype.

Keywords: bootstrap validation; genetic effect modification; macular degeneration; ophthalmology; statistical interaction.

Publication types

  • Clinical Trial
  • Validation Study

MeSH terms

  • Antioxidants / therapeutic use*
  • Complement Factor H / genetics
  • Disease Progression
  • Humans
  • Macular Degeneration / genetics*
  • Macular Degeneration / prevention & control*
  • Proteins / genetics*
  • Zinc / therapeutic use*

Substances

  • ARMS2 protein, human
  • Antioxidants
  • Proteins
  • complement factor H, human
  • Complement Factor H
  • Zinc